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. Author manuscript; available in PMC: 2012 Jan 13.
Published in final edited form as: Arch Ophthalmol. 2010 Dec;128(12):1590–1595. doi: 10.1001/archophthalmol.2010.295

Anti-gamma-enolase autoimmune retinopathy presenting in early childhood

Audrey C Ko 1, Jasmine Hernandez 1, Jason P Brinton 1, Elizabeth A Faidley 1, Sarah A Mugge 1, Marilyn B Mets 2, Randy H Kardon 1,3, James C Folk 1, Robert F Mullins 1, Edwin M Stone 1,4
PMCID: PMC3258021  NIHMSID: NIHMS292490  PMID: 21149784

Abstract

OBJECTIVE

To present the clinical, molecular and serologic findings of a case in which autoimmune retinopathy (AIR) and early onset heritable retinal degeneration were both considered in the differential diagnosis.

METHODS

A three year old female patient presented with clinical findings suggestive of a childhood onset retinal degeneration. DNA and serum samples were collected. The coding regions of 11 genes associated with Leber congenital amaurosis were sequenced. The patient’s serum reactivity to soluble and insoluble fractions of human retinal protein was compared to normal controls (n=32), patients with inflammatory eye disease (n=82), and patients with molecularly confirmed retinal degenerations (n=11). Two-dimensional gel electrophoresis and mass spectrometry were used to identify a protein that corresponded to a reactive band on western blot.

RESULTS

No plausible disease-causing mutations were identified in any of the retinal disease genes tested. However, the patient’s serum showed reactivity to a single retinal antigen of approximately 47kDa. Two-dimensional gel electrophoresis and mass spectrometry revealed the major reactive species to be neuron-specific enolase (NSE). Autoantibodies targeting NSE were not observed in any normal controls or inflammatory eye disease patients. However, anti-NSE activity was found in one child with molecularly confirmed Leber congenital amaurosis.

CONCLUSIONS

This patient’s clinical and laboratory findings coupled with the recently discovered role of anti-NSE antibodies in canine AIR, suggest that autoantibodies targeting NSE are involved in the pathogenesis of her disease.

CLINICAL RELEVANCE

Infection or inflammation within the retina early in life may lead to an autoimmune phenocopy of early-onset inherited retinal degeneration.

INTRODUCTION

Autoimmune retinopathy (AIR) is a pathogenic immunologic process in which circulating antibodies recognize normal retinal proteins and cause retinal degeneration. The retina is a relatively immune privileged tissue that is somewhat isolated from the immune system by the blood-retinal barrier and local inhibition of adaptive and innate immune cells 1, 2. However, several mechanisms can lead to the development of autoantibodies that recognize retinal proteins. Exposure to certain microorganisms can result in the development of antibodies that recognize normal proteins in the retina 3. This mechanism is sometimes known as molecular mimicry. In addition, ineffective peripheral tolerance can result in inadequate suppression of autoreactive lymphocytes that recognize retinal proteins4. These anti-retinal antibodies and self-reactive lymphocytes can gain access to ocular tissues if the blood-retina barrier is disrupted through inflammation or trauma 5.

Patients with AIR usually present with symptoms of sudden visual field loss with a previously normal visual history 6. Although the fundus may initially look normal, visual deficits are often accompanied by severe electroretinographic abnormalities. A diagnosis of AIR is based on clinical evidence coupled with laboratory findings, particularly the finding of anti-retinal antibodies6. Autoantibodies to several retinal proteins have been associated with AIR; most commonly recoverin and alpha enolase 6-9.

The fundus appearance of a patient who has been affected by AIR in the past can be similar to that seen in heritable retinal degenerations like Leber congenital amaurosis and retinitis pigmentosa. It seems likely that some patients, especially young children who are unlikely to report a sudden loss of peripheral vision, are misdiagnosed with an inherited photoreceptor degeneration when in fact their disease is of autoimmune origin. We present a case in which AIR and early onset heritable retinal degeneration were both strongly considered in the differential diagnosis. On the basis of negative genetic testing and positive serology findings, we now believe this young patient to represent an autoimmune phenocopy of an inherited retinal disease.

CASE REPORT

The patient was delivered by Caesarian section after an uncomplicated pregnancy. There was no family history of impaired vision of any kind. Her growth, physical development and cognition are completely normal. In the first few months of life, she was hospitalized for a severe febrile illness. No specific cause for this illness was found and she made a complete recovery. At age three, she told her mother that she could not see when her left eye was covered. This prompted urgent visits to two of the authors (MBM and EMS). Her vision was found to be hand motions OD and 20/20 OS. There was no strabismus or nystagmus and no relative afferent defect was detected at that time. However, the patient’s irides were so dark that the pupil responses were difficult to evaluate with penlight examination alone. Fundus examination revealed normal optic nerves (Figure 1) but significant retinal abnormalities in both eyes consisting of arteriolar narrowing, yellowish macular changes that were more prominent in the right eye than the left, and some perivascular hypopigmentation (Figures 2, 3). There was no anterior segment or vitreous inflammation. A non-sedated electroretinogram was performed and was found to be nonrecordable in both eyes under all stimulus conditions. The patient’s age precluded reliable assessment of her peripheral vision. Although the good central vision OS and the absence of nystagmus were atypical for a congenital photoreceptor abnormality, the abnormal fundus examination and extinguished ERG in both eyes resulted in the provisional diagnosis of Leber congenital amaurosis (LCA). Blood samples were obtained for routine serologic studies and molecular analysis of all known LCA genes (see methods). The serology revealed only mild IgG reactivity to toxocara, herpes simplex type 1, and rubella. These 3 serologic results were of sufficiently low titer that one could interpret them to reflect incidental contact with pets (toxocara), community exposure (herpes simplex), and immunization (rubella) rather than as a cause of the patient’s retinal disease. The patient was reexamined at age 4 and on that visit infrared pupillometry revealed a 2.7 log unit relative afferent pupillary defect. MRI imaging of the brain and orbits ruled out an intracranial cause. Dichromatic pupillometry10 revealed profound retinal dysfunction OD but detectable retinal function OS. The visual acuity and fundus findings on this visit were unchanged from her initial examination. Goldmann perimetry revealed no detectable peripheral vision OD but quite well preserved peripheral vision OS (Figure 4). At this point, the asymmetry of the pupil responses, acuity, visual field and fundus examination caused the authors to consider the possibility of an inflammatory or autoimmune retinal insult as an explanation for her retinal findings. It was suspected that the symmetrical nonrecordability of the unsedated electroretinogram obtained at age 3 was artifactual. However, given the clear asymmetry of her pupil responses and the overall stability of the clinical findings on this visit, the authors chose to defer an electroretinogram under anesthesia. Instead, an additional blood sample was obtained for anti-retinal antibody studies (see below). The patient was most recently seen at age 6 at which time her visual acuity, visual fields and fundus examination were all unchanged from those of her previous visits.

Figure 1.

Figure 1

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Photographs of the right (A) and left (B) optic nerve heads of the patient showing crisp margins and a completely normal salmon color.

Figure 2.

Figure 2

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Montages of retinal photographs taken of the right (A) and left (B) eyes of the patient. The optic nerve heads appear much more pale in these images than those shown in figure 1 because of the exposure settings required to show retinal details in this darkly pigmented fundus. There is arteriolar narrowing in both eyes but it is much more pronounced in the right eye than the left. There is an oval area of yellowish discoloration centered on the macula of the right eye and a much smaller lesion in the left eye just inferior to the fovea. There is a granular appearance to the entire fundus in the right eye which is much less noticeable in the left. There is some perivenous hypopigmentation in both eyes, most noticeable in the left.

Figure 3.

Figure 3

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Higher magnification color photographs of the superotemporal (A) and inferotemporal (B) aspects of the left fundus showing marked perivenous hypopigmentation.

Figure 4.

Figure 4

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Goldmann visual field of the left eye showing a near normal V4e isopter (magenta) and I4e isopter (blue) and moderate symmetrical constriction of the I2e isopter (red).

METHODS

Subjects

This study was approved by the Human Subjects Committee of the University of Iowa. Written informed consent was obtained from all subjects or their parents or guardians. All patients were examined at the University of Iowa by one or more of the authors and these examinations included at a minimum visual acuity and intraocular pressure measurements, slit lamp biomicroscopy, and indirect ophthalmoscopy.

Mutation detection

the coding sequences of eleven genes previously associated with Leber Congenital Amaurosis (CRB1, RDH12, GUCY2D, AIPL1, RPE65, CRX, RPGRIP1, LRAT, CEP290, RD3, TULP1) and the gene encoding the retinal protein against which the patient serum showed reactivity (ENO2) were screened for disease-causing mutations using bidirectional automated DNA sequencing as described previously 11.

Serum Collection

In addition to the samples described in the case report (above), serum samples were also obtained from 11 patients with molecularly confirmed photoreceptor degeneration (9 affected with retinitis pigmentosa; and 2 with Leber congenital amaurosis), and 81 patients with ocular inflammatory disease (10 with autosomal dominant neovascular inflammatory vitreoretinopathy; 7 with acute zonal occult outer retinopathy; 3 with birdshot chorioretinopathy; 14 with multifocal choroiditis; 2 with pars planitis; 29 with ocular histoplasmosis; and 16 with unspecified posterior uveitis). Blood was also collected from 32 control individuals (21 females and 11 males) who had normal healthy retinas and no significant medical history of disease (no visual disturbances, diabetes, cancer, systemic disease, or inflammatory disease). Ten of the control individuals were between 18 and 30 years old, 16 were between 31 and 60 years old, and 6 were more than 60 years old. Blood samples were collected in glass tubes without anticoagulants, allowed to clot, and centrifuged at 1000 × g for 10 minutes. All sera were stored at −80°C until tested.

Preparation of protein samples

Human donor eyes were obtained from the Iowa Lions Eye Bank (Iowa City, IA). Human retina was collected from the entire posterior pole from three donors without known ocular pathology within 6.5 to 17 hours post-mortem. Each whole retina was homogenized in phosphate buffered saline (PBS) containing protease inhibitors (PIC, Roche Complete Kit). The solution was centrifuged at 16,300 × g for 15 minutes, and the aqueous soluble supernatant from this preparation was pooled from all three donors. The remaining pellets were then resuspended in 500 μL of PBS with protease inhibitors and centrifuged for 15 minutes. The supernatants were discarded after each wash, and after three washes the pellets were resuspended in 175 μL PBS with protease inhibitors and with 1% Triton X-100. Pellets were then homogenized and centrifuged at 3000 × g for 2 minutes. The resulting supernatants containing detergent-soluble retinal proteins were pooled from the three donors. Aqueous soluble and insoluble (i.e., detergent soluble) fractions were analyzed as discussed below.

Serum screening

soluble and insoluble retina protein fractions were suspended in a solution containing 1× NuPAGE LDS sample buffer and 1× NuPAGE Reducing Agent (Invitrogen, CA). Proteins were separated with a 1.5mm × 2D well NuPAGE 4-12% Bis-Tris gel at 200V. After electrophoresis, the proteins were transferred from the gel to polyvinylidene fluoride (PVDF) membrane. The membrane was dried overnight and cut into 5mm wide strips that were wetted in methanol and blocked for one hour in 5% non-fat dry milk (NFDM) in PBS. The strips were then each incubated with human serum at a dilution of 1:200 to 1:500 in 2% NFDM for one hour, rinsed with 1× Tris-Buffered Saline with 0.1% Tween 20 (TBST), and washed twice for 10 minutes in TBST. For detection of autoantibody binding, strips were then incubated in a 1:30,000 dilution of horseradish peroxidase conjugated goat-anti-human IgG/A/M antibody (Pierce; Rockford, IL) and washed three times for 10 minutes each in TBST. The membranes were then developed using the ECL Plus Western Blotting Detection System (GE Healthcare, UK). For some experiments, blots were probed with rabbit anti-enolase antibodies (Santa Cruz, H300).

Two dimensional gel electrophoresis and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)

whole soluble retina protein (prepared with protease inhibitors and Triton X-100) from one donor without known ocular pathology was sent for 2D electrophoresis analysis at Kendrick Laboratories (Madison, WI). Ampholytes ranging from a pH of 3.5 to 10 were separated for 13.75 hours at 700V for the first dimension, and the second dimension employed a 10% SDS-PAGE gel. Duplicate gels were run; one gel was silver stained and proteins from the other gel were transferred to a polyvinylidene fluoride membrane. The membrane was probed with serum from the patient to identify the retinal protein bound by antibodies in the serum sample. The resulting film image revealed a single major reactive spot on the membrane. The corresponding silver-stained spot from the duplicate gel was subsequently excised and sent to Columbia University Protein Chemistry Core Facility (New York, NY) for identification via MALDI-MS.

Screening of neuron-specific enolase

sera that showed reactivity to retinal proteins within +/− 5 kDa of the molecular weight of neuron-specific enolase were used to probe a western blot of 117 ng of commercial purified human neuron-specific enolase (Lee Biosolutions, St. Louis, MO).

MOLECULAR RESULTS

Screening of the coding sequences of 11 genes known to cause early onset retinal degeneration (see methods) did not reveal any disease-causing mutations in the patient. However, the patient’s serum intensely labeled a single major band with a molecular weight of approximately 47kDa within the soluble fraction of retina protein(Figure 5). The antibodies that reacted to this band included antibodies from IgG, IgA, and IgM isotypes. This band was not detected in the retinal aqueous insoluble fraction (Figure 5) or in protein samples of RPE-choroid (data not shown).

Figure 5.

Figure 5

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Aqueous soluble (S) and detergent soluble (I) fractions of human retina probed with patient’s serum (left lanes) or with secondary antibody only (right lanes). Note the prominent gamma-enolase band at approximately 47 kDa.

In order to determine the identity of the reactive band, the patient’s serum was used to probe a western blot of proteins separated by 2D gel electrophoresis. The major reactive spot was a 47kDa protein with an acidic isolectric point (Figure 6). Stripping and reprobing of the blot with anti-pan enolase antibodies revealed a smear of reactivity at the same molecular weight as the spot widely distributed across the first dimension, corresponding to all three enolase proteins and their isoforms (data not shown). The retinal protein present in this spot was identified conclusively as neuron-specific enolase (NSE, SwissProt P09104) by MALDI mass spectrometry. Screening of the coding sequence of the patient’s neuron-specific enolase gene (ENO2) showed only normal sequence.

Figure 6.

Figure 6

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Probing of a PVDF membrane containing retinal proteins separated by 2D gel electrophoresis with patient serum. Note the major reactive spot (arrow). The corresponding spot on a silver stained gel was identified as gamma enolase. The approximate positions of the molecular weight markers, based on the corresponding silver stained gel, are indicated on the right side of the panel, and the approximate pH gradient is indicated at the top of the blot.

We then sought to determine whether NSE reactivity is a common finding in patients with retinal disease from our clinic. The sera of 26 patients from the normal controls, patients with ocular inflammatory diseases and patients with molecularly confirmed hereditary retinal degeneration showed reactivity to proteins that had molecular weights similar to that of NSE. These sera were applied to a western blot of purified NSE protein and anti-NSE activity was found in one 7 year old female who had molecularly confirmed Leber congenital amaurosis. However, antibodies directed against NSE were not observed in any controls or ocular inflammatory disease patients.

DISCUSSION

In the pre-molecular era, the diagnosis of Leber congenital amaurosis would not have been entertained for a child with vision better than 20/200. However, as the genes responsible for LCA were discovered, a number of examples were found of children with 20/50 or better visual acuity with mutations in the same genes that cause profound visual loss in other individuals 12. In the patient described in this report, the ophthalmoscopic finding of narrowed arterioles and retinal thinning in both eyes, pink disks, and a nonrecordable electroretinogram, suggested the diagnosis of Leber congenital amaurosis even in the face of 20/20 acuity in the better eye. The profound acuity difference was felt to be secondary to the greater involvement of the macula in the right eye coupled with some amount of superimposed amblyopia. The patient’s very dark irides obscured the large relative afferent papillary defect on her initial evaluation. The perivascular hypopigmentation was somewhat suggestive of periarteriolar preservation of the retinal pigment epithelium seen in some patients with CRB1- or RDH12-associated LCA 13, 14 but careful scrutiny revealed that these perivascular changes were in fact associated with venules not arterioles, more consistent with a previous inflammatory insult with periphlebitis. Infrared pupillometry allowed the afferent defect to be convincingly demonstrated and dichromatic pupillometry and Goldmann perimetry (performed a year later) revealed a degree of functional asymmetry that was more compatible with inflammatory or autoimmune disease than with a primary photoreceptor degeneration. It seems likely that the electroretinographic findings in our patient were an artifact of the unsedated testing conditions. Had we performed the electroretinogram under anesthesia 15, or examined the pupils with infrared videography at the time of her initial visit, the significant asymmetry of our patient’s retinal disease would likely have been recognized at that time.

Plausible disease-causing mutations can be identified in approximately 65% of patients with the clinical diagnosis of LCA and it is currently unknown what fraction of LCA patients without molecular findings have a nongenetic inflammatory or autoimmune disease. That is, since LCA is usually inherited in an autosomal recessive fashion, most families have a single affected child and no family history of a similar disease. If the patient described in this report had had an inflammatory insult in the first few weeks of life that affected both eyes to the same degree as her right eye, she would have undoubtedly have developed sensory nystagmus and exhibited clinical findings that would be very difficult to distinguish from LCA.

Once a nongenetic etiology was suspected, anti-retinal antibodies were sought using western blotting and a single strong band was observed. It has been known for some time that low-titer antibodies to many antigens can develop following compromise of the blood retinal barrier from a variety of different insults 5, 16. Our current thinking is that an autoantibody to a single antigen is more likely to be involved in the pathogenesis of a patient’s disease than antibodies directed against multiple retinal antigens. Isolated anti-NSE antibodies were not observed in any of our 32 normal control subjects or our 81 patients with various forms of uveitis. However we did observe an isolated anti-NSE antibody in a single patient with a molecularly confirmed photoreceptor degeneration – a seven year old girl with CRB1-associated LCA (Cys195Phe and Gly750Asp). Although it is impossible to determine a pathogenic mechanism from two patients, it is interesting that the patient with the anti-NSE autoantibodies had much more severe disease than her older brother who has the same CRB1 genotype. This suggests that the anti-NSE antibody may be augmenting the photoreceptor degeneration in the younger sibling.

Antibodies to another isoform of enolase, alpha-enolase, have also been associated with AIR in humans 17. In vivo and in vitro studies have shown that anti-alpha-enolase antibodies cause the death of retinal cells 18, 19. Anti-alpha-enolase antibodies inhibit the normal function of the targeted enzyme and cause a depleted ATP state within the cell, an increase in intracellular calcium, increased Bax translocation in the mitochondria, induction of cytochrome c release, and ultimately apoptosis 8. When cultured ex vivo or injected in vivo, anti-alpha-enolase antibodies showed the ability to penetrate the layers of the retina and induce the apoptotic death of cells in the inner nuclear layer and the ganglion cell layer 20. The latter finding is consistent with the fairly frequent observation of optic nerve involvement in AIR 21-23.

Although alpha enolase antibodies have been described in autoimmune retinal disease, descriptions of NSE autoantibodies in humans are relatively rare. The major spot bound by the patient’s serum exhibited an acidic isolectric point (pI) consistent with NSE (estimated pI 5.07) but not alpha enolase (estimated pI 7.38) or beta enolase (estimated pI 7.7). The identity of the reactive spot was subsequently confirmed by MALDI-MS as NSE, as well as by the reactivity of the patient’s serum with purified NSE.

Additional evidence for the pathogenicity of the anti-NSE antibodies in the patient described here is the recent identification of similar antibodies in a significant fraction of dogs affected with a canine form of AIR known as sudden acquired retinal degeneration syndrome (SARDS) 24, 25. Braus and colleagues studied the antibody profile of a cohort of dogs diagnosed with SARDS and found that 25% had strong binding of IgG to NSE. None of the 13 control animals showed any serum reactivity to NSE 26. This is also consistent with a study by Maruyama and colleagues who injected anti-NSE serum into the vitreous of Lewis rats and found a lowering of the ERG b-wave amplitude in the treated eyes 27.

In some human AIR patients, intravenous immunoglobulin (IVIg) has been shown to arrest vision loss and improve their visual fields 28-30. Similarly, IVIg treatment of dogs affected with SARDS has also shown promising results 25. We have not used IVIg to treat the patient described in this case report because the visual function in her better eye is so stable.

In summary, it is important for clinicians and scientists who study and care for patients with inherited photoreceptor degenerations to consider the possibility of an autoimmune phenocopy of these diseases, especially for disorders affecting children who are too young to report sudden changes in their vision. Serologic studies of larger numbers of patients with inherited retinal disease as well as additional animal studies will be needed to further test the possibility that anti-NSE antibodies can cause or augment a photoreceptor degeneration.

ACKNOWLEDGEMENTS

The authors thank the patients and control subjects for their participation in this research study. Supported in part by NIH grants EY-017451 (RFM), EY-016822 (EMS), the Doris Duke Charitable Foundation (ACK), the Foundation Fighting Blindness (EMS) and the Grousbeck Family Foundation (EMS). EMS is an Investigator of the Howard Hughes Medical Institute. The authors gratefully acknowledge the Iowa Lions Eye Bank for their support of vision research.

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